Our ability to treat infectious diseases came from the introduction of penicillin 60 years ago. Whilst still a front-line drug for some infections, several pathogenic bacteria have now developed penicillin resistance. As early as the late 1950's Staphylococcus aureus was developing resistance to benzyl-penicillin due to the production of β-lactamase, an enzyme capable of degrading penicillin (reviewed in Stapleton and Taylor (2002) Sci. prog. 85, 57-72). Methicillin, a disubstituted derivative of penicillin, was developed to overcome this resistance. Unfortunately, within the same year that methicillin was used clinically, methicillin resistant S. aureus (MRSA) strains were already detected. Resistance was not due to lactamase production, but to the additional production of a penicillin-binding protein (PBP2α) acquired from another species (Chambers (1997) Clin. Microbil. Rev. 10, 781-791). PBP's are a family of enzymes responsible for cross-linking the glycan chains of the cell wall and are crucial in maintaining bacterial survival.
The over prescription and excessive use of different antibiotics over years has now led to multi drug-resistant MRSA strains. These pose a serious health problem particularly in the USA and Europe. A less publicized area of concern is the irresponsible application of antibiotics for non-human use such as in agriculture and veterinary practice. This has accelerated the development of resistance that can be transferred to human pathogens by plasmids. The cheaply manufactured tetracyclines, in particular, have often been used at sub-therapeutic doses as growth promoters for chickens, pigs and cattle. This practice was banned in Europe in the early 1970's but is still used in the USA and Australia. In 1995, over 3,000 tonnes of tetracyclines were used in the USA alone as animal feed supplements. Human usage was just a few tonnes. Considerable evidence exists suggesting that the use of antibiotics in farm animals has led to resistance development (reviewed in Chopra and Roberts (2001) Microbiol. Mol. Biol. Rev. 655, 232-260).
In the February 2000 report, the National Audit Office noted that hospital-acquired infections (nosocomial) were each year costing the NHS around £1 billion and resulting in at least 5,000 deaths. In the USA alone MRSA costs for 1993 were in excess of $7 billion.
Hospital-acquired infections are now being pursued on several fronts. These range from the practical issues within hospitals such as tackling the factors which inhibit good practice, a more robust approach to antibiotic prescribing, hospital hygiene in general and instituting a system of mandatory surveillance. Therapeutic options are also being investigated. These include production of new structural variants of existing antibiotic classes but with obvious testing against MRSA, combination therapies for example antibiotic with a specific inhibitor that protects the antibiotic from inactivation or removal from the cell (antibiotic efflux is now recognised as a major mechanism of bacterial antibiotic resistance), re-evaluation of earlier pharmacophores and discovery or design of new agents.
Other problems which may be encountered in the use of antibiotics include hypersensitivity reactions and toxicity. Synergistic toxicity may arises when two or more antibiotics are used together, e.g. use of vancomycin and aminoglycoside may lead to renal toxicity.
New methods of combatting bacterial infection are constantly being sought, in improvements in use of current antibiotics and in alternatives to traditional antibiotic technology.